Application of drug metabolism and pharmacokinetics for new drug development

Abstract

Preclinical drug discovery is a time- and labor-consuming work and unfortunately very small number of compounds can be applicable to patients. Moreover, though the cost of new drug development has been increasing for the past many years, the number of approved new drug is relatively fixed (Kola and Landis, 2004). Theoretically it is not possible to develop new drug with complete safety and high efficacy, so the pharmaceutical companies always try to pre-screen potential toxicity of drug candidates. Approximately 50% of lead compounds failed because of insufficient efficacy and 40% attrition of lead compounds is due to safety issues (DiMasi, 1995). In vivo low efficacy and unexpected toxicity are frequently associated with poor drug metabolism and pharmacokinetic profiles (Masimirembwa et al., 2003; Kuppens et al., 2005). Hence, big portion of clinical success of drug candidates could be dependent on DMPK properties of compounds. In fact, DMPK assessment is done at many steps in new drug development procedures, and initial decision could be an important factor for successful drug development. In this special issue, we provide nine outstanding review articles and eleven original articles covering several fields of DMPK and practical pharmaceutics and these articles may strengthen our understanding of current progress in these important research areas. A series of the reviews start with two papers covering animal and human pharmacokinetics: Predicting approaches for human pharmacokinetics using interspecies pharmacokinetic scaling, and accelerated mass spectrometry-based microdosing studies. Kang and Lee introduced the reliable interspecies scaling and prediction methods for various pharmacokinetic parameters and plasma concentration-time (Cp) profiles. The detailed equations were well summarized in tables for the interspecies scaling of total body clearance (CL), volume of distribution at steady state (Vdss) and Cp profiles. The main purpose of interspecies pharmacokinetic scaling is selection of first-in-human dose which is low enough to be safe. Several approaches had been published for this purpose, and the authors thoroughly compared their advantages and limitations in this review. Finally, the authors pointed that these approaches are still highly empirical, so the reliable method improvements are further required for the prediction of human pharmacokinetics (Kang and Lee, 2011). Because of severe temporal and economic standstill in the new drug development, the FDA has made an effort to enhance the productivity by Critical Path Initiative Project since 2004. Exploratory investigational new drug (eIND) studies were introduced for this purpose, and microdosing study (Phase 0 study) could be the core study in this aspect. The purpose of microdosing study is the prediction of human pharmacokinetics in therapeutic doses as early stage as pos